Jaramillo Maria, Mathew Shibin, Task Keith, Barner Sierra, Banerjee Ipsita
Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS One. 2014 Apr 17;9(4):e94307. doi: 10.1371/journal.pone.0094307. eCollection 2014.
This study provides a detailed experimental and mathematical analysis of the impact of the initial pathway of definitive endoderm (DE) induction on later stages of pancreatic maturation. Human embryonic stem cells (hESCs) were induced to insulin-producing cells following a directed-differentiation approach. DE was induced following four alternative pathway modulations. DE derivatives obtained from these alternate pathways were subjected to pancreatic progenitor (PP) induction and maturation and analyzed at each stage. Results indicate that late stage maturation is influenced by the initial pathway of DE commitment. Detailed quantitative analysis revealed WNT3A and FGF2 induced DE cells showed highest expression of insulin, are closely aligned in gene expression patterning and have a closer resemblance to pancreatic organogenesis. Conversely, BMP4 at DE induction gave most divergent differentiation dynamics with lowest insulin upregulation, but highest glucagon upregulation. Additionally, we have concluded that early analysis of PP markers is indicative of its potential for pancreatic maturation.
本研究对确定内胚层（DE）诱导的初始途径对胰腺成熟后期阶段的影响进行了详细的实验和数学分析。采用定向分化方法将人胚胎干细胞（hESCs）诱导为胰岛素分泌细胞。通过四种替代途径调节诱导DE。从这些替代途径获得的DE衍生物进行胰腺祖细胞（PP）诱导和成熟，并在每个阶段进行分析。结果表明，后期成熟受DE定向的初始途径影响。详细的定量分析显示，WNT3A和FGF2诱导的DE细胞胰岛素表达最高，基因表达模式紧密对齐，与胰腺器官发生更相似。相反，DE诱导时的BMP4产生了最不同的分化动力学，胰岛素上调最低，但胰高血糖素上调最高。此外，我们得出结论，对PP标志物的早期分析表明其胰腺成熟的潜力。
